Human immunodeficiency virus type 1 (HIV-1) is a highly mutated virus, which can mutate in different viral particle/envelope regions, at different infection stages, and even exhibit different mutations within the same patient. This high mutation rate is the major reason for the many failures to generate a vaccine against HIV-1. Antibodies induced by numerous experimental vaccines have failed to bind and neutralize HIV-1 viral particles as the HIV-1 virus mutates to escape capture by targeting antibodies. Broadly neutralizing antibodies (bNAbs), such as b12, 447-52D, PGT128, VRC01, 10E8, have been shown to protect in passive immunization and challenge studies in non-human primates. However, to date, there are no vaccines capable of inducing broadly neutralizing antibodies against highly conserved HIV-1 viral epitopes due to the weak immunogenicity of these regions.
In addition, the surface antigen of HIV-1, gp120, is covered by an extensive array of N-linked glycans. These host-derived carbohydrate structures comprise half of the mass of gp120 and shield much of the underlying protein surface, which play essential functional roles in infection and immune evasion. Broadly neutralizing antibodies such as PG9, PG16, PGT128 and 2G12 that bind to the host-derived carbohydrate of gp120 have been shown to provide protection against HIV infection. These results suggest that a vaccine that induces broadly neutralization antibodies to bind against the epitope of carbohydrate of gp120 could prevent HIV infection. However, there are no effective methods to synthesize these host-derived polysaccharides in vitro presenting a similar configuration as host-derived carbohydrate structures of gp120 in vivo. Additionally, the host-derived polysaccharide belongs to T cell independent antigens, which exhibit weak immunogenicity. Thus, it is difficult to induce antibodies specific for host-derived carbohydrates. Despite the various types of vaccines generated to date—including attenuating virus, virus like particle, protein and peptide—all of them have failed to protect against highly mutated and heavily glycosylated HIV-1 infection.
Peptide motif immunization is a technique that is capable of inducing broadly neutralizing antibodies (bNAbs) against highly conserved and functional domains of HIV-1 envelope proteins in the animal models of HIV including in mice, rabbits and rhesus monkeys. Although bNAbs against the weak immunogenicity epitopes were induced by peptide motif immunization in these examples and models as described in WO/2013/040564, it failed to elicit antibodies against the host-derived carbohydrate which was difficult to synthesize in vitro to ensure that its configuration was similar with the native status modified in vivo. In addition, the half-life of the peptide antigen was far shorter than DNA antigen and it failed to induce cellular immunity against HIV-1 infection. Despite that robust cellular immunity against HIV has been induced by a previously constructed plasmid of PD1-P24, neutralization antibodies against HIV-1 have not been elicited via such method. To date, there are no successful vaccines against HIV-1 exhibiting robust cellular immunity. A large number of data indicates that bNAbs are important for inhibiting of HIV-1 infection. Thus, there is a continuing need for an HIV-1 vaccine that induces bNAbs and also exhibits robust cellular immunity against HIV-1.